title: Diminished Memory T-Cell Expansion Due to Delayed Kinetics of Antigen Expression by Lentivectors.
abstract: Memory CD8(+) T lymphocytes play a central role in protective immunity. In attempt to increase the frequencies of memory CD8(+) T cells, repeated immunizations with viral vectors are regularly explored. Lentivectors have emerged as a powerful vaccine modality with relatively low pre-existing and anti-vector immunity, thus, thought to be ideal for boosting memory T cells. Nevertheless, we found that lentivectors elicited diminished secondary T-cell responses that did not exceed those obtained by priming. This was not due to the presence of anti-vector immunity, as limited secondary responses were also observed following heterologous prime-boost immunizations. By dissecting the mechanisms involved in this process, we demonstrate that lentivectors trigger exceptionally slow kinetics of antigen expression, while optimal activation of lentivector-induced T cells relays on durable expression of the antigen. These qualities hamper secondary responses, since lentivector-encoded antigen is rapidly cleared by primary cytotoxic T cells that limit its presentation by dendritic cells. Indeed, blocking antigen clearance by cytotoxic T cells via FTY720 treatment, fully restored antigen presentation. Taken together, while low antigen expression is expected during secondary immunization with any vaccine vector, our results reveal that the intrinsic delayed expression kinetics of lentiviral-encoded antigen, further dampens secondary CD8(+) T-cell expansion.
authors.affiliation: Institute of Dental Sciences, Hebrew University-Hadassah School of Dental Medicine, Jerusalem, Israel.
authors.forename: Karina
authors.initials: K
authors.lastname: Furmanov
authors.forename: Mazal
authors.initials: M
authors.lastname: Elnekave
authors.forename: Abdallah
authors.initials: A
authors.lastname: Sa'eed
authors.forename: Hadas
authors.initials: H
authors.lastname: Segev
authors.forename: Luba
authors.initials: L
authors.lastname: Eli-Berchoer
authors.forename: Darrell N
authors.initials: DN
authors.lastname: Kotton
authors.forename: Gilad
authors.initials: G
authors.lastname: Bachrach
authors.forename: Avi-Hai
authors.initials: AH
authors.lastname: Hovav
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D005822:Genetic Vectors; D007156:Immunologic Memory; D007700:Kinetics; D016086:Lentivirus / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000956:Antigens, Viral